Project Summary Environmental, medical, and endogenously produced DNA damaging agents are ubiquitous, yet, for a given exposure only a subset of individuals experience health effects. This proposal focuses on non-small cell lung cancer (NSCLC) and clinical sensitivity to radiation, a therapeutic agent used to treat NSCLC. These represent two major health effects associated with exposure DNA damage. Our goal is to identify possible markers in blood lymphocytes that can predict NSCLC risk, or the severity of side effects to radiation therapy. It is clear that individuals vary in their capacity to repair DNA lesions, and inefficient DNA repair is a risk factor for cancer and other diseases. However it has thus far not been feasible to use measurements of DNA repair capacity to predict disease risk or acute sensitivity to a particular exposure (such as radiation), because the methods available for measuring DNA repair have not been amenable to making comprehensive assessments of genomic integrity in human populations. Furthermore, efforts to understand inter-individual differences using genomics approaches, such as transcriptional profiling and genome wide genotyping, leave unanswered questions regarding the functional ramifications of the genomic signatures that are identified. We will therefore combine cutting edge technologies for making functional assessments of DNA repair capacity in all of the major pathways with transcriptional profiling and genome wide genotyping to make a comprehensive analysis of genomic integrity in lung cancer patients undergoing radiation therapy and in healthy controls. Lung cancer patients represent a key population of individuals whose disease is often caused by exposure to DNA damaging agents, and has been associated with aberrant DNA repair capacity in multiple pathways, each in separate, previous population studies. Furthermore, treatment with radiation is a defined in vivo human exposure to a complex mixture of DNA damage that provides an opportunity to identify biomarkers that could predict individual sensitivity to DNA damaging agents. Our study is distinguished from previous work by the integration of new functional assays with genomic data. We expect to identify new genomic integrity biomarkers that may predict the radiation dose an individual patient can safely tolerate, as well as biomarkers that may open the door to personalized cancer prevention and surveillance strategies based on identifying individuals who are more likely to develop NSCLC. Because radiation and other DNA damaging agents are a key component of therapy for a wide variety of cancers, and because cancer susceptibility at many sites has been associated with a failure to maintain genomic integrity, the results of this study are likely to be generalizable well beyond the immediate context of non-small cell lung cancer.